Deamination process



United States Patent DEAIVHNATION PROCESS Everett Mvschultz, Broad AxeVillage,-Ambler, Par, as-

signor to Merck & Co., -Inc., a corporation of New Jersey No Drawing.Appiication septomber10, 1952,

Serial N 0. 6089931 2 Claims. (Cl. 260-590) This invention concerns anovel method for the deam'ina'tion of addition salts of beta-tertiaryamino ketones.

In the past, many difliculties have been encountered in deaminatingbeta-tertiary amino ketones. The prior art methods for deaminating saltsof beta-tertiary amino ketones 'iiivolved several steps which were notonly time consuming, but-resulted in low yields of'the ketone sought.The most widely used deamination procedure comprised decomposing thebeta-tertiary amino ketone (I) into an unsaturated ketone (11) and asecondary ami'ne salt by steam distillation or dry distillation. Theunsaturated ketone thus obtained was then hydrogenated catalyticallyyielding 'the next higher homolog (III) of the ketone employed in thepreparation of the beta-tertiary amino ketone. The following reactionformulae illustrate this method. Reaction (A) illustrates a method forthe .production of the beta-tertiary amino ketone, and reactions The"process of deamina'ti-ng the 'bet'a tertiar'y amino ketone by steamdistillation is very time consuming especially when this method isemployed with compounds producing keto'nes of high molecular weight andwhich have, therefore, a low volatility with steam. In addition to thelength of time required to complete this step, a further disadvantage isthat much of the vinyl ketoh'e' II) that is ,iproducedis frequently lostthrough polymerization during distillation. Furthermore, a. second step,hydrogenation, is still required in order to obtain thehomol ogousketone (II-I Hence, the procedure requires considerable time and theyields inmost instances are quite low.

The applicant of the present invention has discovered a simple, one-stepmethod for the deamination of betatertiary amino ketones that provides agood yield of the homologous ketone (III) and overcomes all of thedisadvantages of the methods heretofore employed forthis purpose.According to this novel process, an addition salt of a beta-tertiaryamino ketone is submitted to hydrogenolysis over Raney nickel.Advantageously, th e compound to be deaminated is dissolved or suspendedin an organic solvent and 'the hydrogenation is conducted at elevatedpressure and temperature. Any salt or the beta-tertiary amino ket'o'necan be employed provided it 'the like.

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.2" is not susceptible to reduction under 't-he-reaction'cohdi tions andwill not poison or inactivate the catalyst. Ex amples of such salts arethose formed with mineral acids" asthe hydrohalides, e. g.hydrochloride, sulfates, iphosphates, and the like, or organic-acids-a'sacetic acid, and Suitable solvents are those which will not be effectedby catalytic hydrogenationconditions and which will not exert aninactivating effect upon the catalyst.

Such solvents aref'advantageously organic solvents as lower alkylcarbi'nol's, dioxane and thelike. Preferably absolute ethanol isemployed. The pressure and temperature at which the reaction takes:place will be governed somewhat by the beta-tertiary aminoke'toneemployed. It has been foiind-that-pressures between about 60 to 1'00atmospheres-and temperatures between about to C. and preferably at about80 'C. usually give the maximum yield of ketone (III) in a reasonablyshort period of time.

Under these reaction conditions, one mole of hydrogen per mole ofbeta-tertiary amino ketone 'is absorbed at a moderate rate and then. the"consumption of hydrogen ceases; -Of=cours'e',- if the beta-tertiaryamino ket'one contains an 'olefinic double bond, additionalhydrogenwillbe consumed to" saturate the compound. The products ofthe reaction arethe homologous ketone' (III) and the addition salt of the secondaryamine (IV). This novelp'roe'edure can be represented structurally asfollows:

The reaction mixture, when freedof catalyst, is usually green due todissolved nickel compounds; occasionally it is colorless. In any event,the-color can be removed readily in the subsequent purification. Theketonesobtained are colorless,- they possess very sharp boiling pointsand almost unitormly'yield derivatives that reach a maximum meltingpoint after one recrystallization. Hence, theketoiiesp'roduced are verypure.

In general,- any addition salt of a beta-tertiary amino. ketone havingasan essential portion of its molecule theradical canbe "deaminate'dbythe process of the invention. Substantiallyany' group can be attached tothe carbonyland a carbon -atoms' of the above radical, and NX-Y can bean addition salt of any secondary amine radical, ipro-- vided ineaehinstance noi'group or combination of groups are present which will'beefiected by the catalytic hydrogenation conditions employed in thereaction or which will exert an inactivating "effect upon the catalyst.Of course, if it is desired tohave a substituent attached to either orbothof the carbonyland "tr-carbon atoms which can he removed bycatalytic hydrogenolysis in addition to 'deaminating the beta-tertiaryamino ketone, then 'it only would be necessary to observe that thesesubstituents are not of the type which would inactivate the catalyst. Inaddition, the unsatisfie'i l valence bond attached to'the a-ca'rb'onatom: can be" satisfied with hydrogen.

Inparti'cu-Iar, compounds having'the general formula D Hattie, aromatic;araiipnatie "or-heteio-f cyclic radical; R" is hydrogen or an aliphatic,aromatic;

l atented Jan. 22, 1957 araliphatic, or heterocyclic radical; NX is asecondary amine radical wherein the nitrogen atom is either attached totwo discrete groups or is contained in a heterocyclic ring structure;and Y is a salt forming acid, can be deaminated by the novel process ofthis invention. In practice it will be found that the compounds whichwill be most frequently deaminated by this process, and which have beenfound to undergo deamination most smoothly and with good yields ofhomologous ketone, are compounds of the above general formula wherein Ris a substitutedor unsubstituted-alkyl or -alkyenyl radical,advantageously those of low molecular weight, a substitutedorunsubstituted-aryl or -aralkyl radical, and preferably amononuclear-aryl or -aralkyl radical. Suitable substituents which can beattached to any one or more of the above groups advantageously can bealkyl, alkenyl, aryl, aralkyl, hydroxy,'a1koxy, or any group or groupswhich will not be removed by the catalytic hydrogenation conditions ofthe reaction and will not inactivate the catalyst. Illustrative examplesof the groups represented by R are methyl, normalor iso-propyl, normalorisobutyl, vinyl, allyl, 1,2-diphenylethyl, phenyl, hydroxyphenyl,methoxy-phenyl, benzyl, styryl, and similar groups; R is hydrogen or analkyl, aryl, or aralkyl radical, similarly substituted or unsubstitutedin the manner described above for R, and advantageously those groupswherein the alkyl radical or portion of the radical is lower alkyl.Examples of these groups are methyl, propyl, phenyl, hydroxy-phenyl,methoxy-phenyl, benzyl, styryl, phenethyl, and the like; NX is asecondary-amine radical derived from a dialkyl amine, piperidine,morpholine and the like; and Y is a salt forming acid derived from themineral acids or strong organic acids such as a hydrohalic acid,sulfuric acid, phosphoric acid, acetic acid, and the like. Beta-tertiaryamino ketones having a variety of structures have been employed in thisprocess and in all cases deamination occurred and a good yield of thehomologous ketone (III) was obtained. The age of the Raney nickelcatalyst employed or the use of catalyst from different preparations didnot influence the result of the reaction.

The process of the present invention provides a more economical means tosynthesize ketones of increased chain length via beta-tertiary aminoketones. It is also useful in determining the structures ofbeta-tertiary amino ketones, since from the structure of the homologousketone, which can'be determined easily, the structure of thebeta-tertiary amino ketone can be established.

The following examples illustrate the process of this invention. It isto be understood that the invention is layer became pale yellow. Theether layer was separated and dried over sodium sulfate. The ether thenwas evaporated and the residue distilled yielding 72% of1,1-diphenyl-2-butanone, boiling point 125-l27 C. at 1.5 mm. pressure.

Deamination of the above beta-tertiary amino ketone also occurs when theabsolute ethanol is replaced by an equal quantity of dioxane andfollowing substantially the same procedure described in Example 1, withthe added exception that following completion of the hydro genation, thedioxane is removed by adding the filtered reaction mixture to asufficient amount of water to dissolve the dioxane and amine salt andextracting the ketone into ether. A good yield of1,1-diphenyl-2-butanone, having the same boiling point given for itabove, is thus obtained. Isolation of the homologous ketone can also beeffected by evaporating the dioxane under reduced pressure and workingup the residue in the same manner described in Example 1 following thestep wherein the alcohol is removed.

Deamination of 4-dimethylamino-1,1-diphenyl-2-butanone hydrochloridealso occurred by following the procedure described in Example 1 andconducting the hydrogenation at about 60 atmospheres and at 100 C.Approximately the same yield of 1,1-diphenyl-2-butanone, having the sameboiling point given for it above, was obtained.

By substituting 0.1 mole of the beta-tertiary amino ketone hydrochlorideidentified in each of the examples below for the4-dimethylamino-1,1-diphenyl-2-butanone hydrochloride employed inExample 1, and following substantially the same procedure describedtherein, deamination occurred in each instance and homologous ketones,in the yields given in the following examples, were obtained:

Example 2.Deamination of 4-dimethylamino-l-phenyl-l-methyl-2-butanonehydrochloride produced a 73% yield of l-phenyl-I-methyl-Z-butanonehaving a boiling point of 106-107 C. at 14 mm. pressure, n 1.5030.

Example 3.Deamination of 4 dimethylamino 1- phenyl 1 ethyl 2 butanonehydrochloride produced a 70% yield of 1 phenyl 1 ethyl 2 butanone,boiling point 113-ll4 C. at 13 mm. pressure, n 1.5000.

not limited to the specific conditions recited therein as manyvariations and modifications can be made without departing from thescope of the invention.

Example 1.Deamination of 4-dimethylamino-L1-diphenyl-Z-butanonehydrochloride.-The above mentioned hydrochloride (30.3 grams, 0.1 mole)was suspended in absolute ethanol (150 ml.) and Raney nickel in absoluteethanol (M1 teaspoonful) was added. The mixture was sealed into astainless-steel lined hydrogenation autoclave. Hydrogen was introducedto a pressure of 1,180 pounds per square inch (approximately 80.5atmospheres) and the autoclave was rocked for about three minutes-tosaturate the solvent with hydrogen. The temperature then was raised to80 C. and rocking was resumed. Hydrogen absorption commenced at once andceased after two and one-half hours when 0.1 mole of hydrogen had beenconsumed. After removal of the catalyst by filtration, .the alcohol wasevaporated on a steam bath. The residue on cooling consisted of amixture' of a dark oil and white crystals of dimethylaminohydrochloride. Water was added to dissolve the amine salt and the oilwas extracted with ether. The greenishbrown ether layer was washed with5% hydrochloric acid and with 5% sodium hydroxide solution whereupon thecolor was extracted to the aqueous phase and the ether Example4.-Deamination of 4 dimethylamino lphenyl 1 n propyl 2 butanonehydrochloride produced a 72% yield of 1 phenyl 1 n propyl 2- butanone,boiling point 125 C. at 14 mm. pressure, n 1.4961.

Example 5.Deamination of 4 (1 piperidyl) 1- phenyl l n propyl 2 butanonehydrochloride produced an 86% yield of 1 phenyl 1 n propyl 2- butanonehaving the same physical constants given for it in Example 4. 7

Example 6.-Deamination of 4 dimethylamino lphenyl 1 isopropyl 2 butanonehydrochloride produced a 96% yield of l phenyl l iso propyl 2- butanone,boiling point 118-119 C. at 14 mm. pressure, n 1.4943.

Example 7.Deamination of 4 (l piperidyl) 1- phenyl 1 iso propyl 2butanone hydrochloride (which was catalytically hydrogenated at atemperature of 100 C., but otherwise by the same procedure described inExample 1) produced an 88% yield of 1 phenyl- 1 iso propyl 2 butanonehaving the same physical properties given for it in Example 6.

Example 8.Deamination of 4 dimethylamino 1-' phenyl 1 benzyl 2 butanonehydrochloride produced an yield of 1 phenyl 1 benzyl 2 butanone,-boiling point l23-124 C. at 1.5 mm. pressure, 21 1.5548.

Example 9.Deamination of 4 dimethylamino 3 methy 1,1 diphenyl 2 butanonehydrochloride produced at 51% yield of 3 methyl 1,1 diphenyl 2-"butanone, melting point 72-73 C. after distillation at reduced pressureand crystallization from ligroin.

Example 10.Deamiuation of 4 dimethylamino 1,1- diphenyl l benzyl 2butanone hydrochloride pro duced a 57% yield of 1,1 diphenyl 1 benzyl 2-butanone, boiling point 167-170 C. at 1 mm. pressure; melting point72-73 C. after crystallization from ligroin.

Example 11.-Deamination of 4 dimethylamino 3- phenyl 2 butanonehydrochloride produced an 86% yield of 3 phenyl 2 butanone, boilingpoint 108-110" C. at 21 mm. pressure, n 1.5243.

Example 12.-Deamination of 3 dimethylamino 1- phenyl l propanonehydrochloride produced a 56% yield of 1 phenyl propanone(propionphenone), boiling points 107 C. at 22 mm. pressure and 104 C. at18 mm. pressure, In 1.5091.

Example 13.Deamination of 3 dimethylamino 1- (meta hydroxy phenyl) 1propanone hydrochloride produced a 74% yield of 1 (meta hydroxyphenyl)1- propanone, melting point 75-77 C., after distillation under reducedpressure and crystallization from ligroin.

Example 14.Deamination of 3 dimethylamino 1- anisyl 1 propanonehydrochloride produced a 73% yield of l-anisyl-propanone, boiling point151-152 C. at 16 mm. pressure.

Example 15.-Deamination of 3 diethylamino 1- styryl 1 propanonehydrochloride was conducted as follows: The ketoamine (20.1 grams, 0.075mole) and 3 grams of Raney nickel were added to 100 m1. of absoluteethanol contained in the hydrogenation apparatus described in Example 1.Hydrogen was admitted to a pressure of 900 pounds per square inch at 29C. The temperature was raised gradually while the autoclave was beingrocked and after 45 minutes when the temperature had reached 80, thetheoretical amount of hydrogen (0.15 mole) had been consumed and thereaction was, therefore, complete. The reaction mixture was worked up asin Example 1 to obtain 9.5 grams (79%) of 1- phenyl-B-pentanone; boilingpoint 130-131 C. at 18 mm. pressure, n 1.5068.

All melting points and boiling points are uncorrected.

While the invention has been described by certain specific examples, itis to be understood that variations, such as are described above, can bemade in the reaction condi. tions and in the type of beta-tertiary aminoketone addition salt employed.

What I claimed is:

l. A process for the deamination of a beta-tertiary amino ketone havingthe general formula RI wherein R is selected from the group consistingof aliphatic, aromatic, and araliphatic radicals; R' is selected fromthe group consisting of hydrogen, aliphatic, aromatic, and araliphaticradicals; NX is the residue of a. secondary amine selected from thegroup consisting of dialkylamine and dialkylamines wherein the alkylgroups are linked to form a heterocyclic ring with the nitrogen atom,and Y is a salt forming acid selected from the group consisting ofmineral acids and strong organic acids by hydrogenolysis over Raneynickel yielding a product having the general formula wherein R and Rhave the meaning assigned above.

2. A process for the deamination of a beta-tertiary amino ketoneaccording to claim 1, wherein the hydrogenolysis over Raney nickel takesplace in the presence of an organic solvent and at elevated pressure andtemperature.

Adkins: Reaction of Hydrogen, etc. 1937, pp. 90, 91, 96.

1. A PROCESS FOR THE DEAMINATION OF A BETA-TERTIARY AMINO KETONE HAVINGTHE GENERAL FORMULA